Though the activated microglia/macrophages (M?) are known to contribute to secondary brain injury after stroke, M? are also instrumental in the repair process. To explain such contrasting roles, two M? phenotypes, harmful/M1 and healing/M2, have been proposed. Importantly, the M1 M? can be polarized to M2 and vice versa. While various molecules derived from stroke-injured cells have the propensity to polarize M? toward M1 type (causing the generation of pro-inflammatory cytokines and pro-oxidants), other molecules (e.g. generated by T cells), such as IL-4, IL10 or TGF, polarize M? toward the M2 type. The M2 M? control the cleanup processes (phagocytosis- mediated removal of toxic and pro-inflammatory cellular debris), and the production of trophic factors. Thus, the source of toxicity and the biological and physical barriers hampering neural reorganization are removed, while providing trophic support governing neuronal sprouting (the repair process). Without the M2 M?, healing would not be possible. While both M1 and M2 M? phenotypes co-exist shortly after stroke, M2 phenotype weakens within 2-3 days allowing M1 type to dominate. This adversely affects the brain cleanup, repair, and recovery, while boosting cytotoxicity. Exploring the mechanisms underlying such processes and therapeutic approaches aiming at rectifying the M2 polarization loss are the subjects of this proposal. Our novel findings indicate that in response to ischemia, neurons synthesize and release IL-4 (canonical M2 polarizing cytokine) during the first 3 days of stroke, followed by a decline in both IL-4 and M2 M? levels. IL-4-induced M2 M? polarization requires the activation of RXR-PPAR? pathway. The administration of IL-4 or agonists of PPAR? and RXR (rectifying factors) for 5 days, starting at 1d post stroke, improves recovery and neuronal re-wiring. Loss of PPAR? in M? impedes recovery. Aim 1. Elucidate, in vitro, the role of neurons in M? polarization and post stroke repair: IL-4- medaited PPAR?:RXR-executed process involving phagocytosis (cleanup) and trophic stimulation. Hypothesis: Neurons act as sensors of injury and generate IL-4/IL13 that signals to microglia to induce M2 polarization, while suppressing M1 phenotype associated with cytotoxicity. Aim 2. Elucidate, in vivo, the basis of IL-4 signaling to PPAR?:RXR, and apply them into clinically relevant approaches targeting the phagocyte-mediated brain cleanup, remodeling, and post- stroke recovery. Hypothesis: Because the initial polarization toward the healing M? phenotype after stroke, driven by neuronal production of IL4/IL13, is lost within few days after stroke, approaches aiming at restoring IL-4-medaited signaling, such as via recombinant IL-4 and PPAR?:RXR activation (molecular targets of IL-4 in M?), to rectify M2 polarization loss will assist in post stroke recovery.